Stable aqueous drug suspensions and methods for preparation thereof

ABSTRACT

Finely divided drug particles are coated with a lipid or bioadhesive polymer to form microspheres having a particle size of about 550 micrometers or less, and coated with two or more enteric coatings, at least one of which is water insoluble, to form microcapsules. The resultant microcapsules can be suspended in an aqueous solution to form stable oral doses of the drug.

FIELD OF THE INVENTION

This invention relates to aqueous suspensions of encapsulated drugshaving improved stability during storage, but which are designed forsystemic environmentally-activated release at desiredpost-administration times and places, and processes for making suchsuspensions.

BACKGROUND OF THE INVENTION

Drugs such as amoxicillin, ampicillin, penicillin V and erythromycin areantibacterial drugs which are available for oral dispensation in agelatin capsule containing a specified dosage amount of the drug. Forpatients who have difficulty swallowing capsules, e.g., the very youngand the very old, the drugs can be suspended in an aqueous solution,such as a sugar type syrup. However, the aforementioned drugs are quiteunstable in water, even when stored at temperatures of about 4° C., andvery unstable at room temperature. Thus the drug solutions orsuspensions have a very short shelf life, even at low temperatures.Further, they have an unpleasant taste which makes them unpalatable.

Beta-lactam antibiotics are orally inactive, and must be combined withan enhancer to promote their absorption into the body of the patient.Such enhancers are known, for example see U.S. Pat. No. 4,525,339, andinclude aliphatic fatty acids or acid glycerides. The fatty acids aregenerally C₂ to C₁₈ fatty acids, which can be straight or branchedchain, saturated or unsaturated, their mono-, di- or triglycerides ormixtures thereof, and can also be partial or total esters of propyleneglycol, polyethylene glycol and carbohydrates of C₂ to C₁₂ fatty acidsand pharmaceutically acceptable esters and ethers of said glyceride.Encapsulating the drug in the enhancer is known also.

It would be quite advantageous to be able to formulate theabove-described drugs, in a liquid-deliverable form, which would,nevertheless, be stable over the course of long term storage, i.e., forup to about 18 months, even at room temperature. To achieve this elusiveobjective without compromising the efficacy of the drugs, the drugswould have somehow to be isolated from the water in the storage/deliverymedium, yet be released at the appropriate time and in the desiredsystemic environment of a recipient's body. In satisfying theseobjectives, drugs could be coated uniformly and completely with awater-impervious coating. In order for the encapsulated drug particlesto stay suspended in an aqueous solution or emulsion for administrationin liquid form, the individual particle size of the encapsulated drugparticles would have to be very small, on the order of 1500 micrometersor less; otherwise the drug particles would settle out of the solutionor suspension, and the dosage would be inaccurate.

Therefore, a suitable coating or encapsulant material must be imperviousto water (to withstand long-term storage), but for efficacious patienttreatment must dissolve in the stomach or other appropriate portion ofthe digestive tract, depending on the drug to be administered and thedosage required. Coatings having particular solubility characteristicscan be used to provide controlled or delayed release of the drug in thepatient.

Unfortunately, no one encapsulant coating is known to date that iseffective to carry out all of the above-described objectives. Thus thereis a need to be able to apply more than one encapsulant material,successively and uniformly, over very small particle size granules ofthe drug to be administered. Thus, it would be highly desirable toprovide a practicable method for preparing small microspheres, on theorder of about 500 micrometers, at the center of each of which lieindividual drug particles. Each drug particle is encapsulated bysuccessive encapsulants, each of a material which dissolves in aparticular systemic environment in order to expose the next, moreinterior encapsulant layer for subsequent reaction at a distinctly newsystemic environment, and ultimately for exposing the drug particle atthe appropriate time and systemic loci.

SUMMARY OF THE INVENTION

Applicant has discovered that it is possible and practical tomanufacture microspheres (or "microcapsules") at the center of which liedrug particles of up to about 550 microns in size, each drug particlebeing encapsulated by a succession of uniform and completelyencapsulating coatings of matrix material of a lipid or a bioadhesivepolymer. At least one of the multiple coatings is impervious tomoisture, to produce microcapsules which are insoluble in water at aboutneutral pH, but which are soluble at acid pH. The microcapsules have amaximum particle size of about 1500 micrometers so they will staysuspended in an aqueous solution. The microcapsules can be tailored tohave other features, such as successive layers cf encapsulants havingdiffering solubility characteristics.

The microspheres are made using high speed rotation, e.g., a rotatingdisc method, that forms uniform, spherical particles of the requiredsize. The microspheres are encapsulated with two or more coatings havingdiffering solubility characteristics. The resulting water imperviousmicrocapsules can be admixed with aqueous solutions to form stablesuspensions or mixtures that have a long shelf life in a concentrationto provide dosage amounts of the drug that can be taken orally.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a cross sectional view of a high speed rotating disc systemfor preparing the microspheres of the invention.

FIG. 2 is a cross sectional view of a centrifugal extrusion apparatusalso used for preparing the microspheres and microcapsules of theinvention.

FIG. 3 is a cross sectional view of an air suspension chamber forencapsulating the microspheres of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The microspheres and microcapsules described in this invention can beprepared using a variety of methods, including but not limited to, arotating disc system, spray drying, a centrifugal extrusion nozzledevice, an air suspension cooler, phase separation and solventevaporation. In the following paragraphs some of the procedures that canbe used to prepare the microcapsules described hereinafter are set forthin detail. Variations will be known to those skilled in the art.

Microspheres of the desired particle size, i.e., less than 550micrometers, and preferably between about 250 to 500 micrometers, can bemade using a high speed rotating disc system as shown in FIG. 1.

Referring to FIG. 1, the high speed rotating disc system 10 comprises anemulsion feed tube 12 which is situated over and feeds onto a rotatingdisc 14. The disc 14 is rotated by means of a motor 16. The disc 14 andthe motor 16 are enclosed in a chamber 18. The chamber 18 serves to dryor cool and solidify the microspheres and to collect them in acollection area 20. The chamber 18 is also fitted with a filter 22 andan exhaust system 24. The disc 14 is situated some distance above thecollection area 20 to allow time for solidification of the microspheres.

In operation, a slurry of the solid drug particles, which are finelydivided below about 100 micrometers, and a suitable matrix, e.g., alipid or bioadhesive composition, is fed to the feed tube 12 and droppedonto the rotating disc 14. Droplets or microspheres are thrown out fromthe periphery of the disc 14 due to the centrifugal forces developed bythe high speed rotation of the disc 14, and fall by gravity to thecollection area 20 of the chamber 18. The small spherical liquiddroplets or microspheres are dried/cooled and solidified during thisfree fall, and are then collected. If desired, the microspheres can besieved to collect a desired particle size distribution. For a disc about4 inches in diameter rotating at about 2000 rpm, and a drug particlesize of about 50 micrometers, the majority of the resultant microsphereshave a particle size of about 105 to 500 micrometers. Control of therotational speed of the disc 14 provides control over the size and sizedistribution of the microspheres.

Alternatively, and particularly suitable for hot melt matrix materials,microspheres can be formed in a centrifugal extrusion apparatus 110 asshown in FIG. 2. Referring to FIG. 2, the feed mixture or slurry of drugparticles in the heated matrix material is fed through the center tubeof a concentric feed tube 112 by means of a seal (not shown) to arotating head 114 fitted with one or more nozzles 116. A rotating shaft118 rotates the head 114 at high speed by means of a motor 119. Amechanical stirrer (not shown) can be used in the feed tank (not shown)prior to pumping through the feed tube 112 to provide continuousstirring of the drug particles in the hot melt matrix. As the head 114rotates, the slurry of the drug in the matrix material flows through theinner orifice of the nozzle, creating a stream of the drug particlesuniformly dispersed in the molten matrix material. This extruded rodbreaks into individual particles due to the high speed rotation of thehead 114. The coated drug particles are cooled and solidify to form thedesired microspheres as they free fall into the collection area 120. Thesize of the resultant microspheres can be controlled and is dependentupon the feed rate, the speed of rotation of the head 114 and the sizeof the nozzle openings. Microsphere particle sizes of from about 250 to500 micrometers can be made readily.

In order to form the microcapsules of the invention, the microspheres asprepared above are encapsulated in one or more coatings, at least one ofwhich is water-impervious.

The microcapsules can be prepared using the apparatus as shown in FIG.2, except using an additional feed line into the head 114. The slurry ofthe drug particles in the heated matrix material is fed through thecenter tube of the concentric teed tube 112. The desired encapsulantmaterial and any additives are fed through a separate feed line to theouter tube 113 of the feed tube 112 to the head 114. The additional feedline is provided to supply the encapsulant material, e.g., a waterimpervious polymer dissolved in a solvent, as well as any optionalmaterials desired such as colorants, flavorings, surfactants and otheradditives as desired. The slurry of the drug particles in the matrixmaterial is fed along with the encapsulant material, to the head 114.The rotation of the head 114 causes the encapsulant or encapsulantmixture to flow through the outer orifice of the nozzle and the drugslurry to flow through the inner orifice of the nozzle, creating a rodof the drug slurry encased in a sheath of the encapsulant materials. Ifan organic solvent is used in the encapsulant, it is vaporized and canbe collected through the exhaust (not shown) for disposal or, recycledas desired.

The microcapsules of the invention can also be made in a modified airsuspension coater apparatus as shown in FIG. 3. The air suspensioncoater 210 comprises a chamber 212 fitted with an air distribution plate216 through which an air stream passes. A feed line 220 for supplyingthe encapsulant material is connected to a hydraulic or pneumatic nozzle224 which atomizes the encapsulant material into small droplets whichcoat the microspheres.

In operation, the microspheres 226 to be coated are fed through an entryport 228 in the chamber 212. An air stream supplied by means of a bloweris fed into the chamber 212 and passes through the air distributionplate 216 to carry the microspheres smoothly past the head 224 forcoating with encapsulant, and then up and over a coating partition 230where the coated microspheres are dried and cooled during free fall backoutside the coating partition 230 to begin another cycle past the nozzle224. The nozzle 224 is designed to atomize the coating material to allowa uniform, thin coating to be applied. In the course of multiple passesof the microspheres past the nozzle 224, the encapsulant materialuniformly coats the microspheres to the desired thickness. By changingthe encapsulant materials which are fed to the nozzle 224, successivelayers of desired encapsulant compositions are applied. Control of theair volume end temperature, atomizing conditions and rate of applicationensures a high degree of uniformity of the coatings from batch to batch.Further, the closed system of the apparatus 210 provides excellentcontrol of the conditions within the coater.

Virtually any non-liquid medicinal agent can be processed usingApplicant's invention. However, the greatest benefit arises fromprocessing drugs which are highly unstable in water and which would bemore efficaciously or easily administered in an aqueous medium. This maybe because of a patient's difficulty in taking tablets, or because ofsome other, more aesthetic characteristic of the drugs (chalkiness, badtaste). For these and other reasons as well, Applicant's inventionparticularly benefits those who administer and receive antibacterialdrugs including erythromycin or erythromycin ethyl succinate, and thepenicillins, their salts, esters and hydrates, such as amoxicillintrihydrate, ampicillin trihydrate, penicillin V potassium and the like.These drugs are unstable in water, are presently administered in tabletform, and are unpalatable to most patients if simply admixed into asyrup medium.

These drugs are supplied in solid form. If a drug is supplied in alarger particle sizes than are desired for processing according toApplicant's invention, milling can effectuate the desired particle sizesprior to coating with a lipid coating.

As used herein, the term lipid includes fatty acids, whether saturatedor unsaturated, such as monobasic aliphatic carboxylic acids which formesters with glycerol or other alcohols to make fats, oils, waxes andother lipids. Also included are the esters and ethers of glycerides, theesters formed by reaction of the fatty acids with glycerol, such estersformed from pharmaceutically acceptable weak acids such as tartaric acidand its diacetyl derivative, acetic acid, ascorbic acid and citric acid,or one having a monophosphate group to yield the mono-phosphate ester.Suitable ethers are formed by reaction of the mono- or diglyceride witha functionally reactive lower alkyl, alkenyl, alkynyl, aryl orsubstituted aryl group to produce the corresponding pharmaceuticallyacceptable ether, as is known in the art. Polyhydric alcohols such asoctanol or a carbohydrate polyol, e.g., sucrose, are also useful in thepresent invention.

The matrix material can also be a bioadhesive polymer that will providea delayed release of the drug. The bioadhesive polymer attaches to thestomach lining or mucin coating of the stomach, where it hydrates and isabsorbed, thereby releasing the drug particles.

Suitable bioadhesive polymers include adhesive materials such asgelatin, polycarbophil polymers, and Chitosan, commercially availablefrom Protan of Norway. These matrix materials provide a delivery systemwhich may provide a long acting dosage form by providing a reduced rateof emptying of the drug in the stomach, improve bioavailability of thedrug, improved therapy, and increase the contact time of the drug in thedesired absorption area.

The microspheres are made into microcapsules by means of one or moreenteric coatings. The enteric coatings can be tailored to have the drugabsorbed in the body as desired, but at least one layer of entericcoating must be water insoluble at normal pH. Most antibiotics are meantto be absorbed in the intestinal tract, and thus must be protected fromthe high acid content gastric fluid of the stomach. Thus successivecoatings may be insoluble in highly acid environments, i.e., pH belowabout 5, but soluble in less acid environments, i.e. pH about 5.5 to 7.5or higher.

Examples of known enteric coating materials useful herein includecellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,shellac, methacrylic acid and methacrylic acid esters and zein.Partially hydrogenated vegetable oils, stearic acid, hydrogenated tallowtriglycerides, food grade metal stearates, tallow and mixtures thereofand the like are used as lipids, carriers and modifiers for themicrospheres. Suitable partially hydrogenated vegetable oil material iscommercially available as Durkee 17 and Durkee KLX from Van den Burgh.Emersol 6349 stearic acid is commercially available from EmoryIndustries. Hydrogenated tallow triglycerides are commercially availableas Grocol 600-E from A. Gross and Co. Suitable tallow flakes arecommercially available from Anderson Clayton/Hank Products, Inc. Aseries of methacrylic acid or methacrylic acid esters commerciallyavailable as EUDRAGIT coatings, trademarks of Rotim Pharma GmbH ofWesterstadt, West Germany, have varying degrees of esterification, andare soluble at varying pH. Thus drugs which are meant to be absorbed inthe small intestine will be encapsulated in a first enteric coating thatis insoluble in water but soluble in acidic environment, e.g., thestomach, and a second enteric coating which is insoluble in the low pHgastric fluid of the stomach, but soluble in the less acid environmentof the small intestine. For example, EUDRAGIT L-100 is insoluble atneutral pH but soluble at a pH less than 5.5; EUDRAGIT L-100-55 andL-30D are soluble at pH greater than. 5.5. Metal stearates incorporatedinto these shell materials can increase water repellency. Other entericcoatings are known which are less soluble and can provide release of thedrug over time, as will be known to those skilled in the art.

To provide both water impermeability, protection of the drug in thestomach and release in the intestine, and delayed release in theintestine, a series of enteric coatings will be applied to themicrospheres. The outer layer will be water insoluble at normal pH, butwill dissolve in the stomach (pH less than. 5.5). The next layer will beinsoluble at low pH in the stomach, but will dissolve and release thedrug in the intestine (pH greater than 5.5). A third layer can providedelayed release until the drug enters the upper gastrointestinal tract,where the pH is higher again.

The enteric coatings are dissolved in an organic solvent, suitably oneapproved for medicinal use, such as acetone, methylene chloride, or thelower alcohols such a ethanol, or mixtures of such solvents, and appliedto the microspheres as above. The organic solvents are removed byevaporation during the processing of the microcapsules.

The amount of coating applied to the microspheres is not critical, andcan vary from 5 to 30% by weight of the microcapsule. It is importantthat the enteric coating be applied uniformly over the microsphere toensure that the microspheres are protected from moisture, and that agiven dosage of the drug will be released by the coatings at theappropriate portion and time in the digestive tract. Too thick a coatingwill delay dissolution of the coating and release of the drug.

The enteric coatings can also contain conventional additives such assuspending agents, emulsifying agents, essential oils, preservatives,flavoring or coloring agents and the like, as is known to one skilled inthe art. Such additives can retain a desired texture, retard hydrationor dehydration of the microsphere ingredients, and provide a uniformcolor and appearance.

The invention will be further described in the following examples, butthe invention is not meant to be limited to the details thereof. In theexamples, percent is by weight.

The actual erythromycin and erythromycin ethyl succinate content of themicrospheres was determined by high pressure liquid chromatography(HPLC).

Actual amoxicillin trihydrate content in the microspheres was determinedusing an iodimetric titration method, see Code of Federal Regulations:Food and Drugs, Vol 21, Chap 1 Part 436.204 (1988), 291.

EXAMPLE 1

Using the rotating disc apparatus of FIG. 1, a slurry containing 30.0%of Erythromycin USP, 44.1% of Emersol 6349, 18.9% of Durkee 17 and 7.0%of aluminum stearate EA was heated to 180° F. and fed to the discmaintained at a temperature of 160° F.

The resultant microspheres had a particle size distribution of 4.3%particles of less than 105 microns; 84.9% particles of 105-250 microns;and 10.8% particles of 250-355 micrometers.

An assay of the microspheres having a particle size of 250-355micrometers determined the actual Erythromycin content to be 20.9%.

EXAMPLES 2-13

The procedure of Example 1 was followed except varying the matrixcomposition and temperature. In these Examples, 30.0% of Erythromycinwas employed. The data summarizing the matrix composition, the matrixtemperature, particle size and weight % distribution obtained and theactual Erythromycin content in the microspheres are summarized below inTable I. In the Table, D17 represents Durkee 17; E6349 representsEmersol 6349; G 600-E represents Grocol 600-E; Zn St represents foodgrade zinc stearate; Mg St represents food grade magnesium stearate; AlSt represents food grade aluminum stearate; and A 84K represents Atmul84K.

                                      TABLE I                                     __________________________________________________________________________         Matrix         Particle Size                                                                              Actual %                                     Example                                                                            Composition                                                                            Temp. °F.                                                                    Micrometers                                                                          Weight %                                                                            Erythromycin                                 __________________________________________________________________________    2    70.0%                                                                             D17  155   250-355                                                                              100   25.3                                         3    56.0%                                                                             E6349                                                                              155   105-250                                                                              18.4  25.7                                              14.0%                                                                             G600-E     250-355                                                                              68.4                                                                   355-500                                                                              13.2                                               4    52.5%                                                                             E6349                                                                              155   105-250                                                                              35.8  24.5                                              17.5%                                                                             D17        250-355                                                                              64.2                                               5    50.4%                                                                             E6349                                                                              180   105-250                                                                              35.7  24.5                                              12.6%                                                                             G600-E     250-355                                                                              64.3                                                    7.0%                                                                              Zn St                                                                6    44.1%                                                                             E6349                                                                              180   105-250                                                                              61.6  21.3                                              18.9%                                                                             D17        250-335                                                                              38.4                                                    7.0%                                                                              Zn St                                                                7    63.0%                                                                             D17  190   105-250                                                                              38.1  20.9                                              7.0%                                                                              Zn St      250-355                                                                              61.9                                               8    50.4%                                                                             E6349                                                                              190   105-250                                                                              71.4  26.5                                              12.6%                                                                             G600-E     250-355                                                                              28.6                                                    7.0%                                                                              Mg St                                                                9    44.1%                                                                             E6349                                                                              190   105-250                                                                              52.9  27.3                                              18.9%                                                                             D17        250-355                                                                              47.1                                                    7.0%                                                                              Mg St                                                                10   63.0%                                                                             D17  190-200                                                                             105-250                                                                              23.4  27.3                                              7.0%                                                                              Mg St                                                                              250-355                                                                             55.8                                                                    355-500                                                                             20.8                                                      11   50.4%                                                                             E6349                                                                              180   105-250                                                                              83.0  21.3                                              12.6%                                                                             G600-E     250-355                                                                              17.0                                                    7.0%                                                                              Al St                                                                12   63.0%                                                                             D17  190-200                                                                             105-250                                                                              57.1  26.5                                              7.0%                                                                              Al St      250-355                                                                              23.1                                                             355-500                                                                             19.8                                                      13   63.0%                                                                             D17  190   105-250                                                                              25.8  27.3                                              7.0%                                                                              A84K       250-355                                                                              74.2                                               Control                                                                            100%                                                                              D17  155   <105   15.2  --                                                         105-250                                                                             58.7                                                                    250-355                                                                             26.1                                                      __________________________________________________________________________

All of the microspheres were satisfactory.

EXAMPLE 14-22

The procedure for Examples 2-13 was followed except using 23% ofErythromycin. The data are summarized in Table II below, where thesymbols are the same as for Table I.

                  TABLE II                                                        ______________________________________                                               Matrix                Particle Size                                    Example                                                                              Composition  Temp. °F.                                                                       Micrometers                                                                            Weight %                                ______________________________________                                        14     56.0%   E6349    190    105-250  15.9                                         14.0%   G600-E          250-355  63.5                                         7.0%    Zn St           355-500  20.6                                  15     52.5%   E6349    190    105-250  39.9                                         17.5%   D17             250-355  60.1                                         7.0%    Zn St                                                          16     70.0%   D17      190    105-250  23.9                                         7.0%    Zn St           250-355  76.1                                  17     56.0%   E6349    190    105-250  30.4                                         14.0%   G600-E          250-355  59.8                                         7.0%    Al St           355-500  9.8                                   18     52.5%   E6349    190    105-250  67.5                                         17.5%   D17             250-355  32.5                                         7.0%    Al St                                                          19     70.0%   D17      190-200                                                                              <105     8.2                                          7.0%    Al St           105-250  46.9                                                          250-355                                                                              44.9                                           20     56.0%   E6349    190    105-250  67.0                                         14.0%   G600-E          250-355  33.0                                         7.0%    Mg St                                                          21     52.5%   E6349    190    105-250  58.9                                         17.5%   D17             250-355  41.1                                         7.0%    Mg St                                                          22     70.0%   D17      190    105-250  10.4                                         7.0%    Mg St           250-355  71.4                                                                 355-500  18.2                                  ______________________________________                                    

All of the microspheres were satisfactory.

EXAMPLES 23-34

Using the apparatus of FIG. 2 at a head speed of 2000 rpm, a headtemperature of 190° F. and a shell composition temperature of 180° F., aslurry of the drug in a matrix material was encapsulated with a singlelayer of various encapsulant compositions to produce microcapsules.Equal amounts by weight of the drug slurry and encapsulant wereemployed; thus the theoretical amount of Erythromycin was 15% in themicrocapsules, which were sieved to collect a particle size of 250-500micrometers for analysis. The data are summarized in Table III belowwhere the symbols are the same as for Table I and N 060 representsNeutrene 060 triglycerides.

                  TABLE III                                                       ______________________________________                                               Encapsulant  Slurry        Actual                                      Example                                                                              Composition  Composition   Erythromycin                                ______________________________________                                        23     90%     D17      Ex3         8.7                                              10%     Zn St                                                          24     80%     E6349    Ex3         9.5                                              20%     G600-E                                                         25     80%     E6349    Ex2         5.4                                              20%     G600-E                                                         26     100%    D17      Ex2         6.1                                       27     90%     D17      Ex2         5.6                                              10%     Zn St                                                          28     90%     D17      Ex2         6.1                                              10%     Mg St                                                          29     100%    D17      Ex3         --                                        30     90%     D17      Ex3         --                                               10%     Mg St                                                          31     80%     E6349    56.0% E6349   6.7                                            20%     N060     14.0% N060                                                          30% Erythromycin                                                32     100%    D17      56.0% E6349   --                                                              14.0% N060                                                          30% Erythromycin                                                33     90%     D17      56.0% E6349   --                                             10%     Zn St    14.0% N060                                                          30% Erythromycin                                                34     90%     D17      56.0% E6349   --                                             10%     Mg St    14.0% N060                                                          30% Erythromycin                                                ______________________________________                                    

EXAMPLES 35-47

Using the apparatus of FIG. 3, the microspheres prepared as in Examples1-22 were encapsulated with two or more layers of various encapsulantcompositions to produce microcapsules. The enteric coatings weredissolved in a solvent mixture, as shown, to which was optionally addeda dyestuff, FD&C #1 Lake Blue, or FD&C #6 Lake Yellow. EUDRAGIT E-100provides stability in liquid suspension and in the mouth, (pH about 7)and is soluble in the stomach (pH less than 5.5). EUDRAGIT L-100-55 willprovide protection in the stomach and release the drug in the intestinaltract (pH over 5.5).

The data relating to the application of the coatings are summarized inTable IV below.

                                      TABLE IV                                    __________________________________________________________________________                Shell Coating Composition % By Weight                             Microsphere Eudragit ™                                                                        Eudragit ™    Methylene                                                                           Colorant                                                                            Assay;                        Example                                                                            Example                                                                              L-100-55                                                                             E-100  Ethanol                                                                            Acetone                                                                            Chloride                                                                            #1 #6 Microcapsules                 __________________________________________________________________________    35   14     4             19.2 76.8       0.1                                                    4      24.0      72.0     0.1                                                                              17.2                          36   2      4             19.2 76.8       0.1   25.6                                             4      24.0 72.0          0.1                              37   3      4             24.0 72.0       0.1   25.4                                             4      24.0      72.0     0.1                              38   4      4             24.0 72.0       0.1   26.7                                             4      24.0      72.0     0.1                              39   4      4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              24.2                          40   6      4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              24.5                          41   7      4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              25.2                          42   8      4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              26.0                          43   9      4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              26.0                          44   10     4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              26.0                          45   11     4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              25.6                          46   12     4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              26.3                          47   1      4             24.0 72.0       0.1                                                    4      24.0 72.0          0.1                                                                              25.2                          __________________________________________________________________________

The data relating to the amount of the coatings applied is given belowin Table V. where the result was obtained from a measurement of theamount of shell solution per weight of microsphere sample used duringthe coating process. The resultant microcapsules were in the 250 to 500micrometer size range.

                  TABLE V                                                         ______________________________________                                                      Weight % Shell                                                  Example         Inner   Outer                                                 ______________________________________                                        36              14.0    13.9                                                  43              13.0    13.3                                                  44              13.0    13.8                                                  45              13.0    13.2                                                  46              13.0    13.1                                                  47              13.0    13.6                                                  ______________________________________                                    

EXAMPLE 48

Microcapsule samples made as in Examples 35-47 were evaluated forstability in simple syrup solution by storing for 1 and 4 weeks underaccelerated shelf-life conditions at 37° C. The amount of antibioticfound in the syrup was determined. The data are summarized below inTable VI.

                  TABLE VI                                                        ______________________________________                                        Microcapsules,  % Release % Release                                           Example         1 Week    4 Weeks                                             ______________________________________                                        35              <1.0*     6.2                                                 36              0.11      2.4                                                 37              <1.0*     2.5                                                 38              <1.0*     2.5                                                 39**            <1.0*     3.0                                                 40              0.97      2.6                                                 41              0.74      2.0                                                 42              1.3       2.9                                                 43              0.76      3.1                                                 44              0.74      2.0                                                 45              0.81      2.2                                                 46              0.74      1.9                                                 47              0.64      1.6                                                 ______________________________________                                         *Estimated                                                                    **These samples were then shaken at 37° C. for 48 hours. The %         release for Example 39 was 3.6%; the % release for Example 47 was 1.8%.  

It is apparent that the microcapsules of the invention are stable inaqueous solution for long periods of time, even under acceleratedtemperature conditions.

EXAMPLE 49 Part A

Microspheres were made following the procedure of Example 1 using 40.0%of erythromycin ethyl succinate within a 60% Durkee 17 matrix. Thematrix temperature was 235° F.

The product contained 39.4% of particles 106-250 micrometers in size;and 60.4% of particles 250-355 micrometers 10 in size.

The actual amount of the antibiotic found in the microspheres was 31.2%.

Part B

The procedure of Example 35 was followed to make microcapsules of themicrospheres of Part A. The first coating was made using EUDRAGIT L-30Dand a second coating of EUDRAGIT E-100 using a solvent mixture of 72.0parts of methyLene chloride and 24.0 parts of ethanol. The microcapsulescontained 20.0% of erythromycin ethyl succinate.

EXAMPLES 50-55

The procedure of Example 1 was followed to prepare microspheres exceptthat the drug employed was amoxicillin trihydrate in varying amounts.The data on microsphere preparation is summarized below in Table VII.

                                      TABLE VII                                   __________________________________________________________________________    Matrix              Particle Size,                                                                             % Amoxicillin Trihydrate                     Example                                                                            Composition                                                                            Temp. °F.                                                                    Micrometers                                                                          Weight %                                                                            Theoretical                                                                         Found                                  __________________________________________________________________________    50   44.1%                                                                             E6349                                                                              170   250-355                                                                              100   30.0  24.0                                        18.9%                                                                             D17                                                                       7.0%                                                                              Al St                                                                51   50.4%                                                                             E6349                                                                              200   106-250                                                                              35.9  37.0  Not-Tested                                  12.6%                                                                             Tallow     250-355                                                                              64.1                                                        Flakes                                                               52   63.0                                                                              D17  200   250-355                                                                              100   37.0  32.5                                   53   63.0%                                                                             D17  210   106-250                                                                              50.8  32.0  26.7                                                       250-355                                                                              49.2                                               54   68.0%                                                                             D17  200   106-250                                                                              50.8  32.0  26.7                                                 250-355                                                                             49.2                                                      55   68.0%                                                                             D17  200   250-355                                                                              100   32.0  21.8                                   __________________________________________________________________________

EXAMPLES 56-60

The microspheres as in Examples 50-55 were encapsulated following theprocedure of Example 35. The data relating to the encapsulations aresummarized in Table VIII below:

                                      TABLE VIII                                  __________________________________________________________________________    Shell Coatings, % By Weight      Solvent                                      Microsphere Eudragit ™                                                                        Eudragit ™                                                                        Eudragit ™    Methylene                                                                           Colorant                                                                            Assay;                 Example                                                                            Example                                                                              L-100-55                                                                             E-100  L-30D  Ethanol                                                                            Acetone                                                                            Chloride                                                                            #1 #6 Microcapsules          __________________________________________________________________________    56   50     4                    24.0 72.0       0.1                                             4             24.0 72.0          0.1                                                                              21.6                   57   51     4                    24.0 72.0       0.1   --                     58   52            4             24.0      72.0        15.9                                             100                    0.1                                             4             24.0      72.0     0.1                       59   54            4             24.0      72.0        --                     60   55            4             24.0      72.0     0.1                                                                              16.4                                             100                    0.1                                             4             24.0      72.0     0.1                       __________________________________________________________________________

EXAMPLE 61

The microcapsule samples made as in Example 56 using the microspheres asmade in Example 50 were evaluated in simple syrup solution by storingfor one, four and eleven weeks under accelerated shelf life conditionsat 37° C. The amounts of antibiotic found in the syrup after vigorousshaking is as follows: 0.0% release after one week; 3.1% release afterfour weeks and 26.5% release after eleven weeks.

It is apparent that the microspheres of the invention can 10 beencapsulated with multiple coatings as desired using the processes ofthe invention. The resultant microcapsules are small in size, are waterimpervious, and can be tailored so that the drug is protected in aqueoussolutions, and can be released as desired, and when desired, to optimizethe drug's effectiveness. The invention also provides a means ofdispensing a water unstable drug in an aqueous solution that is stableand which can be stored at room temperature for extended periods oftime.

I claim:
 1. A method for producing drug delivery microcapsules havingsuccessive, systemic environment-activated release phases comprising thesteps of:selecting a microsphere core particle;encapsulating said coreparticle in a first coating formed of a first coating material whichfirst material, prior to dissolution, is liquid impervious, is waterinsoluble at a pH of less than about 5.5, but water soluble at a pHgreater than 5.5; and encapsulating said core particle and said firstcoating with a second coating formed of a second coating material whichis water insoluble at neutral pH but soluble at a pH of less than 5.5.2. The method of claim 1 wherein said core particle is of a drug whichis unstable in water.
 3. The method of claim 1 wherein said coreparticle, with said first and second coatings applied thereto is lessthan about 1500 micrometers in any dimension.
 4. Method of claim 2,wherein the water-unstable drug is ampicillin, amoxicillin, penicillinV, or the salts, esters or hydrates thereof.
 5. The method of claim 1,wherein the microsphere core particles comprise a water-unstable drug ina matrix of a lipid selected from the group consisting of partiallyhydrogenated vegetable oils, stearic acid, hydrogenated allowtriglycerides, food grade metal stearates, tallow and mixtures thereof.6. The method of claim 1 wherein said first material comprises apolymethacrylic acid or a polymethacrylic acid ester.
 7. The stabledosage form of claim 1, wherein each microcapsule has a particle size of250 to 550 micrometers.
 8. The stable dosage form of claim 1, whereineach microsphere core particle has a particle size of 105 to 500micrometers.
 9. The method of claim 1, wherein each microsphere coreparticle has a particle size of 250 to 355 micrometers.